9. Project Summary: Recent studies have demonstrated that consuming high fructose corn syrup (HFCS)- or sucrose-sweetened beverages increased lipid/lipoprotein risk factors for CVD in healthy adults compared with iso-caloric amounts of glucose or low-fat milk. The longest of these studies, which utilized a 6-month intervention, also showed increased liver and muscle TG and increased visceral adipose deposition. Neither of these studies found differences in weight gain between subjects consuming HFCS/sucrose beverages compared with control beverages. These results suggest that it is not just excess calories and weight gain that mediate the effects of dietary sugar/fructose on the development of metabolic disease; rather, dietary sugar per se is also a contributor. However, it is not known whether consumption of excessive amounts of sugar can increase risk factors for metabolic disease in the absence of positive energy balance and weight gain, nor whether the adverse effects of sugar consumption are exacerbated by weight gain. This study will test the overall hypotheses that consumption of HFCS-sweetened beverages increases risk factors for metabolic disease even when consumed with an energy-balanced diet that prevents weight gain, and that risk factors are increased to a greater extent when HFCS-sweetened beverages are consumed in a setting of positive energy balance that results in weight gain. We will also test the hypothesis, that under blinded, controlled, dietary conditions, consumption of HFCS-sweetened beverages will increase energy intake and body weight gain more than consumption of aspartame-sweetened beverages. We will measure risk factors and processes associated with metabolic disease in 3 groups of young, healthy adults who will consume 1) 25% of energy requirement as HFCS-sweetened beverages with an energy-balanced diet; 2) 25% of energy requirement as HFCS- sweetened beverages with an ad libitum diet; or 3) aspartame-sweetened beverages with an ad libitum diet for 8 weeks. All diets, formulated to achieve a comparable macronutrient intake (55% energy as carbohydrate, 35% fat, 15% protein) among all 3 experimental groups, will be provided to the subjects throughout the entire study. We hypothesize that consumption of HFCS-sweetened beverages with the energy-balanced diet will result in adverse metabolic effects, despite the absence of weight gain. Consumption of HFCS-sweetened beverages with the ad libitum diet will result in increased energy intake and body weight gain compared with aspartame-sweetened beverages, and will also result in adverse metabolic effects that are more marked than with consumption of HFCS-sweetened beverages with the energy-balanced diet. These results will demonstrate that consumption of HFCS-sweetened beverages increases risk for metabolic disease both directly, via the adverse effects of fructose on lipid and carbohydrate metabolism, and indirectly, via the effects of HFCS-sweetened beverages to promote excess energy intake and body weight gain. These findings will have the potential to influence dietary guidelines and public health policy.